STING activation reverses lymphoma-mediated resistance to antibody immunotherapy
Lekh N. Dahal,Lang Dou,Khiyam Hussain,Rena Liu,Alexander Earley,Kerry L. Cox,Salome Murinello,Ian Tracy,Francesco Forconi,Andrew J. Steele,Patrick J. Duriez,Diego Gomez-Nicola,Jessica L. Teeling,Martin J. Glennie,Mark S. Cragg,Stephen A. Beers +15 more
TL;DR: Potent adjuvants like STINGa, which can improve FcγR activatory:inhibitory (A:I) ratios on TAM, are appealing candidates to reprogram TAM and curb tumor-mediated immunosuppression, thereby empowering mAb efficacy.
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Abstract: Tumors routinely attract and co-opt macrophages to promote their growth, angiogenesis and metastasis. Macrophages are also the key effector cell for monoclonal antibody (mAb) therapies. Here we report that the tumor microenvironment creates an immunosuppressive signature on tumor-associated macrophages (TAM) which favors expression of inhibitory rather than activating Fcγ receptors (FcγR), thereby limiting the efficacy of mAb immunotherapy. We assessed a panel of TLR and STING agonists (a) for their ability to reprogram macrophages to a state optimal for mAb immunotherapy. Both STINGa and TLRa induced cytokine release, modulated FcγR expression and augmented mAb-mediated tumor cell phagocytosis in vitro. However, only STINGa reversed the suppressive FcγR profile in vivo, providing strong adjuvant effects to anti-CD20 mAb in murine models of lymphoma. Potent adjuvants like STINGa which can improve FcγR activatory:inhibitory (A:I) ratios on TAM are appealing candidates to reprogram TAM and curb tumor-mediated immunosuppression, thereby empowering mAb efficacy.
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Fc-Engineering for Modulated Effector Functions-Improving Antibodies for Cancer Treatment.
TL;DR: The underpinning structure-function relationships and how the Fc has been engineered to produce an increasing number of antibodies that are appearing in the clinic with augmented abilities to treat cancer are revealed.
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Therapeutic Antibodies: What Have We Learnt from Targeting CD20 and Where Are We Going?
TL;DR: Current and future developments relating to enhanced effector function, such as the ability to form multimers on the target cell surface, are discussed, chiefly involving the combination of anti-CD20 mAbs with various other agents to resensitize patients to treatment.
Antibodies to Costimulatory Receptor 4-1BB Enhance Anti-tumor Immunity via T Regulatory Cell Depletion and Promotion of CD8 T Cell Effector Function.
Sarah L. Buchan,Lang Dou,Marcus Remer,Steven G. Booth,Stuart N. Dunn,Chester Lai,Chester Lai,Monika Semmrich,Ingrid Teige,Linda Mårtensson,Christine A. Penfold,H.T. Claude Chan,Jane E. Willoughby,C. Ian Mockridge,Lekh N. Dahal,Kirstie L. S. Cleary,Sonya James,Anne Rogel,Päivi Kannisto,Mats Jernetz,Emily L Williams,Eugene Healy,Eugene Healy,J. Sjef Verbeek,Peter Johnson,Björn Frendéus,Mark S. Cragg,Martin J. Glennie,Juliet C. Gray,Aymen Al-Shamkhani,Stephen A. Beers +30 more
TL;DR: Dual anti‐tumor activities for antibodies to the co‐stimulatory receptor 4‐1BB, which depend on antibody isotype and Fc&ggr;R availability are revealed, and antibodies engineered to harness both Treg cell depleting and effector cell agonism properties show potent anti‐Tumor activity in preclinical models.
141
Boosting therapeutic potency of antibodies by taming Fc domain functions
Tae Hyun Kang,Sang Taek Jung +1 more
TL;DR: It is reported that monoclonal antibodies can be engineered to activate effective immune cell types to treat a particular disease, and engineering can also increase mAbs’ persistence in the blood, enabling less frequent administration.
Targeting Cytosolic Nucleic Acid-Sensing Pathways for Cancer Immunotherapies.
TL;DR: How cGAS–STING and RIG-I–MAVS pathways have been targeted for cancer treatment in preclinical translational researches is discussed and a targeted selection of recent clinical trials employing agonists of cytosolic NA-sensing pathways is presented showing how these pathways are currently being targeted for clinical application in oncology.
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